Abstract
G protein-coupled receptors (GPCRs) are classically characterized as cell-surface receptors transmitting extracellular signals into cells. Here we show that central components of a GPCR signaling system comprised of the melatonin type 1 receptor (MT1), its associated G protein, and β-arrestins are on and within neuronal mitochondria. We discovered that the ligand melatonin is exclusively synthesized in the mitochondrial matrix and released by the organelle activating the mitochondrial MT1signal-transduction pathway inhibiting stress-mediated cytochromecrelease and caspase activation. These findings coupled with our observation that mitochondrial MT1overexpression reduces ischemic brain injury in mice delineate a mitochondrial GPCR mechanism contributing to the neuroprotective action of melatonin. We propose a new term, “automitocrine,” analogous to “autocrine” when a similar phenomenon occurs at the cellular level, to describe this unexpected intracellular organelle ligand–receptor pathway that opens a new research avenue investigating mitochondrial GPCR biology.
Funder
HHS | National Institutes of Health
David Scaife Family Charitable Foundation
Cotswold Foundation Fellowship Award
Agence Nationale de la Recherche
Fondation de la Recherche Medicale Equipe
Institut National de la Santé et de la Recherche Médicale
Institut National des Sciences de l'Univers, Centre National de la Recherche Scientifique
La Region Centre
Publisher
Proceedings of the National Academy of Sciences
Cited by
286 articles.
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